The impact of HIV on the oral cavity has shifted from mediating syndromes associated with an immunocompromised immune system, such as candidiasis, to oral manifestations including, but not limited to HPV associated warts and severe aphthous ulcer stomatitis. The central hypothesis presented here is that HIV related oral complications arise from perturbations in innate and adaptive immune defense mechanisms in concert with the epithelium and that predisposition towards oral manifestations may lie in genes that regulate the expression of innate immune molecules. Human beta defensins (hBDs) have been a focus of our group's research in HIV. We have discovered that oral epithelial cell-derived hBDs can be (1) induced by HIV, (2) they inhibit the ability of the virus to infect immunocompetent cells, (3) they interact with specific chemokines and toll-like receptors resulting in regulation of adaptive immune cells, (4) chronic HIV infection and/or highly active antiretroviral therapy (HAART) predisposes oral mucosae to both cellular and innate immune impairment, and (5) amongst the innate repertoire of molecules, hBDs are unique in that there is interpersonal variability in expression levels owing to copy number variation. Our multidisciplinary program is synergistic through the direct collaboration and interaction of our faculty and core facilities. Investigators in Project #1 and Project #2 will cooperatively design, produce, and share altered forms of hBDs that will be utilized in structure/function studies that explore hBD interactions with chemokines and toll-like receptors. The investigators from Projects #I and #3 will design and implement studies that explore the cross-talk between epithelial cells and antigen presenting cells. Projects #3 and #4 will share tissue isolated from oral warts and other HIV-associated oral complication(s) to examine their protein and genomic profiles. Thus, these projects are highly integrated on both a theoretical and collaborative basis and involve an integrated multidisciplinary approach. Finally, projects will be supported by the Proteomics/Bioinformatics Core (Core B), and information gathered through the Program Project will be subjected to rigorous scientific scrutiny through meetings between the Proteomics/Bioinformatics Core and an External Advisory Panel that will be organized through the Administrative Core (Core A). [unreadable]